Toward inclusive therapy with CFTR modulators: Progress and challenges

Abstract

Cystic fibrosis is caused by gene mutations that result in an abnormal Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein on the surface of cells. CFTR modulators are a novel class of drugs that directly target the molecular defect. CFTR modulators include potentiators that result in improved activity of the channel; correctors that help the protein traffic to the cell surface properly; and readthrough agents that restore full-length CFTR by suppression of premature termination codons, among other novel classes more recently established. While some of these drugs, CFTR potentiators in particular, have provided remarkable improvements for CF patients, others have yet to achieve profoundly improved outcomes, and many CF patients are not yet impacted by CFTR modulators due to lack of knowledge regarding susceptibility of their mutations to treatment. One limitation to expanding these types of therapies to the maximum number of patients with CF is the lack of rigorously validated clinical biomarkers that can determine efficacy on an individual basis, as well as few pre-clinical tools that can predict whether an individual with a rare combination of mutant alleles will respond to a particular CFTR modulator regimen. In this review, we discuss the various groups of CFTR modulators and their status in clinical development, as well as address the current literature on biomarkers, pre-clinical cellbased tools, and the role of pharmacometrics in creating therapeutic strategies to improve the lives of all patients with cystic fibrosis, regardless of their specific mutation.

A defective flexible loop contributes to the processing and gating defects of the predominant cystic fibrosis‐causing mutation

“…We also found that low temperature and corrector C18 stimulated protein expression of not only ∆F508‐CFTR but also some other CFTR deletion mutants that miss a residue in the H3‐H4 loop. Therefore, even if drug cocktails of CFTR correctors and potentiators provide a promising cure for people with CF (75), our data highlight the possibility that small molecules that correct defects in the H3 helix and H3‐H4 loop might rescue both the processing and gating defects of ∆F508‐CFTR.…”

Cystic fibrosis: novel therapies, remaining challenges

“…Based on the defects in CFTR as shown in Figure , these agents have been classified into various classes that reflect the activity or function of a specific agent. CFTR potentiators, such as ivacaftor, increase the activity of CFTR at the cell surface, whereas correctors such as lumacaftor and tezacaftor improve the processing and trafficking of CFTR to the cell surface . Although not yet in clinical use, other approaches include increasing the expression, and thus amount, of CFTR by using ‘CFTR amplifiers’ or agents that target the ribosome to restore full‐length CFTR .…”

“…CFTR potentiators, such as ivacaftor, increase the activity of CFTR at the cell surface, whereas correctors such as lumacaftor and tezacaftor improve the processing and trafficking of CFTR to the cell surface . Although not yet in clinical use, other approaches include increasing the expression, and thus amount, of CFTR by using ‘CFTR amplifiers’ or agents that target the ribosome to restore full‐length CFTR . This latter approach has been achieved with aminoglycosides, but potential toxicity of traditional agents, such as gentamicin, has seen the development of novel aminoglycosides with reduced toxicity …”

“…Although not yet in clinical use, other approaches include increasing the expression, and thus amount, of CFTR by using ‘CFTR amplifiers’ or agents that target the ribosome to restore full‐length CFTR . This latter approach has been achieved with aminoglycosides, but potential toxicity of traditional agents, such as gentamicin, has seen the development of novel aminoglycosides with reduced toxicity …”

“…26 As clinical experience and confidence have grown for CFTR modulation therapeutics, the FDA has accepted adaptation of clinical programs at an earlier stage in the lifecycle of a product (e.g. by enabling lumacaftor/ivacaftor to be licensed by open label data in [6][7][8][9][10][11] year olds rather than the double-blind data required for ivacaftor at the same stage of development). Both the EMA and FDA have shown commitment to those aged 2-5 years by accepting open label safety, pharmacokinetic and pharmacodynamic data.…”